US20030133987A1 - Drug nanoparticles from template emulsions - Google Patents

Drug nanoparticles from template emulsions Download PDF

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Publication number
US20030133987A1
US20030133987A1 US10/340,079 US34007903A US2003133987A1 US 20030133987 A1 US20030133987 A1 US 20030133987A1 US 34007903 A US34007903 A US 34007903A US 2003133987 A1 US2003133987 A1 US 2003133987A1
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Prior art keywords
drug
solvent
drug particles
template emulsion
water
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US10/340,079
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Sonke Svenson
Chris Tucker
Steve Lubetkin
Jonathan Evans
Steve Rosenberg
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Individual
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles

Definitions

  • the present invention relates to the preparation of aqueous emulsions, and in particular to the preparation of such emulsions containing poorly water soluble pharmaceutical products or drugs.
  • Bioavailability is a term meaning the degree to which a pharmaceutical product, or drug, becomes available to the target tissue after being administered to the body. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water. For example, upon oral administration poorly water soluble drugs tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation.
  • exposing a drug substance to excessive mechanical shear or exceedingly high temperatures can cause the drug to change or lose activity due to decomposition of the active compound, or due to recrystallyzation processes, i.e., formation of different crystalline polymorphs or transformation, at least in part, from the crystalline to the amorphous state, as described by Florence et al, Effect of Particle Size Reduction on Digoxin Crystal Properties, Journal of Pharmaceutics and Pharmacology, Vol. 26, No. 6, 479-480 (1974), and R. Suryanarayanan and A. G. Mitchell, Evaluation of Two Concepts of Crystallinity Using Calcium Gluceptate as a Model Compound, International Journal of Pharmaceutics, Vol. 24, 1-17 (1985).
  • wet milling techniques always result in the presence of a fraction of larger particles, which affects the time for the particles to completely dissolve.
  • U.S. Pat. Nos. 6,017,559 and 6,074,986 teach the use of templating agents to control particle size in pesticide formulations.
  • neither the '559 patent nor the '986 patent addresses the concerns with bioavailability of drug substances.
  • the present invention is a method for producing a micron-sized or submicron-sized drug which comprises preparing a template emulsion comprising water and a templating agent; preparing a drug-containing mixture comprising a drug substance; and combining the template emulsion with the drug-containing mixture to form a template emulsion loaded with drug particles.
  • the template emulsion loaded with drug particles may be used as is or if a solid dispersion of the drug substance is desired, the solvent may be removed from the template emulsion.
  • the present invention is drug particles produced by a method which comprises preparing a template emulsion comprising water and a templating agent; preparing a drug containing mixture comprising a drug substance; and combining the template emulsion with the drug containing mixture to form drug particles in the template emulsion.
  • the present invention has several advantages.
  • the present invention only imparts high temperature and mechanical stress, i.e., high shear, necessary to form small droplets, to the template emulsion and not to the drug containing mixture, thereby reducing the potential harm to the bioactivity of the drug substance.
  • the use of a templating agent provides improved control over the particle size and size distribution of the resulting drug particles.
  • FIG. 1 is a graph depicting the X-ray powder diffraction pattern of an embodiment of the present invention.
  • FIG. 2 is a graph depicting the in vitro dissolution profile of an embodiment of the present invention.
  • FIGS. 3 A- 3 C are graphs depicting the in vivo bioavailability of an embodiment of the present invention.
  • the template emulsions used in the present invention are defined as being a stable two-phase dispersion comprising a continuous aqueous phase and a discontinuous phase comprising a non-aqueous material and a stabilizer in an amount sufficient to depress migration of the non-aqueous material through the aqueous phase, thereby diminishing or preventing particle growth of the template emulsion, for example through Ostwald ripening, wherein the stabilizer is soluble in the discontinuous phase but insoluble in the aqueous phase.
  • the template emulsions used to prepare the micron-sized and submicron-sized drug particles of the present invention are prepared using techniques well known in the art for forming emulsions and comprise a templating agent and water in an amount of from 0.5 to 50, preferably from 2 to 20, and most preferably from 5 to 10 percent by weight.
  • the template emulsion droplets have the proper size. As the drug containing mixture is combined with the template emulsion, the drug substance and solvent will migrate into the templating agent droplets, increasing the droplet size by a consistent and predictable amount. The size of the droplets of the templating agent in the template emulsion thus determines the size of the resulting drug particles by setting a boundary for the particle growth of the resulting drug particles.
  • the particle size distribution of the resulting drug particles in the template emulsion can be controlled by appropriate control of the droplet size distribution of the templating agent in the template emulsion.
  • the shape of the particle size distribution curve of the resulting aqueous emulsion reflects closely the shape of the particle size distribution curve of the templating agent employed.
  • agitation In order to form the appropriate droplet size for the templating agent in the template emulsion, some form of agitation is preferably used.
  • the type of agitation used is not critical, and any type of conventional agitation used to make emulsions can be used, so long as the appropriate droplet size for the templating agent in the template emulsion is achieved.
  • suitable agitation means include stirring, homogenization, and the use of a microfluidizer, micromixer etc.
  • the templating agent is a liquid or oil that is poorly water soluble.
  • suitable templating agents include alkyl substituted benzenes such as toluene, xylene or propyl benzene fractions, and mixed naphthalene and alkyl naphthalene fractions; mineral oils; triglyceride oils such as cottonseed oil, olive oil, soybean oil and vegetable oils; hydrated vegetable oils; dialkyl amides of fatty acids, particularly the dimethyl amides of fatty acids; chlorinated aliphatic and aromatic hydrocarbons such as 1,1,1,-trichloroethane and chlorobenzene; esters of glycol derivatives such as the acetate of the n-butyl, ethyl, or methyl ether of diethyleneglycol; ketones such as isophorone and trimethylcyclohexanone; and alkyl acetates such as hexyl or heptyl a
  • the preferred templating agents are those that are either listed by the FDA as generally regarded as safe (GRAS) or easily removable by standard procedures, i.e., cottonseed oil, olive oil, soybean oil and vegetable oils; mineral oils; alkyl acetates; and toluene.
  • GRAS generally regarded as safe
  • the template emulsion further comprises at least one stabilizer.
  • the stabilizer has several functions.
  • the stabilizer operates as an emulsifying agent depressing the migration of the non-aqueous material through the aqueous phase, thereby stabilizing the template emulsion by diminishing or preventing droplet growth of the template emulsion.
  • the stabilizer also inhibits crystal growth, aggregation and agglomeration of the drug particles.
  • suitable stabilizers may be polymers, homopolymers or co-polymers, for example those described in “Polymer Handbook” 3 rd Edition edited by J. Brandrup and E. H. Immergut.
  • suitable homopolymers and co-polymers include polyolefins and substituted polyolefins such as polyethylene, polypropylene, polybutene, polybutadiene, and chlorinated derivatives thereof; polyacrylates and polymethacrylates; polydisubstituted esters; polyvinyl ethers, chlorides, acetates, and carboxylate esters such as polyvinyl butyrate caprylate, laurate, stearate, benzoate; polystyrene; natural rubber and hydrochlorinated rubber; ethyl, butyl, and benzyl celluloses; cellulose esters; and combinations of these polymers.
  • suitable polymers are those polymers which can also function as a surfactant but yet are insoluble in the continuous aqueous phase, such as nonionic polyalkylene glycol/(poly)carboxylic acid compounds; A-B-A block-type surfactants; and high molecular weight esters of natural vegetable oils such as the alkyl esters of stearic and oleic acids.
  • nonionic polyalkylene glycol/(poly)carboxylic acid compounds such as nonionic polyalkylene glycol/(poly)carboxylic acid compounds; A-B-A block-type surfactants; and high molecular weight esters of natural vegetable oils such as the alkyl esters of stearic and oleic acids.
  • very hydrophobic small molecules i.e., hexadecane
  • Preferred stabilizer are those that are a part of the GRAS-list, i.e., alkyl esters of stearic and oleic acids.
  • the stabilizer can be in the physical state of a liquid or oil, or can be a solid.
  • the composition of the stabilizer or mixture of stabilizers will depend upon the need to exclusively interact with the dispersed phase but not interact with the continuous phase.
  • the stabilizers may be employed in an amount from 0.1 to 90, preferably from 0.5 to 50 percent by weight of the dispersed phase.
  • the stabilizer is a surfactant.
  • Surfactants that can be advantageously employed herein can be readily determined by those skilled in the art and include various nonionic, anionic, cationic, and amphoteric surfactants, or a blend of those surfactants.
  • Preferred surfactants are those which significantly reduce the tendency for the oil droplets of the discontinuous phase to agglomerate.
  • nonionic surfactants include the polyalkylene glycol ethers and condensation products of aliphatic alcohols, aliphatic amines, or fatty acids with ethylene oxide or propylene oxide; polyvinyl alcohols of different molecular weights and degree of hydrolyzation; polyvinyl pyrrolidones; and the surfactants of the Brij, Tween, and Span series.
  • Anionic surfactants include salts of alkyl aryl sulphonic acids, sulphated polyglycol ethers, and ethers of sulphosuccinic acid.
  • Cationic surfactants include quaternary ammonium compounds and fatty amines. The surfactant is generally employed in an amount of from 0.1 to 15, more preferably from 2 to 10, and most preferably about 5 percent by weight of the total composition.
  • the template emulsion is combined with a drug containing mixture which is defined herein as being a drug solution or a coarse drug emulsion.
  • a drug solution comprises a drug substance and a water immiscible solvent
  • a coarse drug emulsion comprises a drug substance, a water immiscible solvent, and water.
  • Mixing of the template emulsion and the drug containing mixture is preferably carried out at a temperature of from ambient to 70° C., more preferably ambient to 50° C., and most preferably at ambient temperature.
  • the appropriate temperature chosen will depend upon the melting points of the materials used in the preparation and the temperature stability of the drug.
  • the template emulsion and the drug containing mixture can be combined using any technique known in the art of combining liquid streams. Some form of agitation is preferably applied, although the process does not require agitation to successfully load the drug substance into the template droplets.
  • the type of agitation used is not critical, and any type of conventional agitation can be used.
  • the drug substance is generally employed in an amount of from 1 to 50, more preferably from 15 to 30 percent by weight of the drug containing mixture used to load the template droplets with the drug.
  • the appropriate drug-to-solvent ratio mostly depends on the solubility of the drug in the chosen solvent.
  • the drug substance is in essentially pure form.
  • the drug substance is preferably poorly soluble in water with a solubility range of between 0.1 and 10 percent by weight, and dispersible in at least one liquid medium.
  • Preferred drug substances include those intended for oral administration including, for example, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiacinotropic agents, contrast media, corticosterioids, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diagnostic imaging
  • the drug containing mixture utilizes at least one solvent such that when the drug containing mixture and the template emulsion are combined, the solvent forces the drug to migrate into the templating agent.
  • Solvents preferred for use in the drug containing mixture must have low water solubility, preferably between 0.01 and 2.0 percent by weight, and low vapor pressure, preferably between 0.5 and 500 mm Hg.
  • Suitable solvents include alkanes and chlorinated alkanes such as dichloromethane, aliphatic and aromatic ethers, alipatic and aromatic esters, such as IBA, aliphatic and aromatic ketones, aromatics such as toluene, and combinations thereof.
  • the drug substance will migrate into the templating agent droplets, forming drug particles in the template emulsion.
  • the size of such drug particles are in the submicron to micron range, between 0.2 and 20, more preferably between 0.5 and 10, and most preferably between 0.5 and 5 microns, as measured using light scattering techniques.
  • the process of the present invention further comprises the step of removing the solvents.
  • the vast amount of the solvents can be removed from the template emulsion by evaporation using standard evaporation techniques, causing the drug substance to precipitate or crystallize.
  • the drug particle size is hereby controlled by the size of the template emulsion droplets.
  • the process of the present invention comprises an additional solvent removal step and in particular, a water removal step.
  • the final solvent removal can be done using any technique known in the art of drying, i.e., freeze-drying, spray-drying, fixed or fluidized bed drying, or flash drying; or the solid drug substance particles can be isolated from the aqueous phase by standard separation techniques.
  • compositions of the inventions may also include optional excipients such as standard fillers, binders, or disintegrants readily known by those skilled in the art in amounts of 0 to 15 percent by weight of the total composition.
  • the resulting drug particles are desirably redispersible in water with nearly the same particle size as the particles before redispersion.
  • the particles are redispersed in water such that the resulting redispersed particle size is less than 5 microns.
  • a template emulsion comprising cottonseed oil (2.5 g), polyvinylpyrrolidone 55 kD (7.5 g), methyloleate (1.1 g), and water (12.5 g) was prepared with high shear mixing. A fraction (4 g) of the template emulsion was diluted with water (32 g), giving template emulsion droplets with a mean diameter of 0.19 microns as measured by light scattering. The template emulsion was mixed at ambient temperature with a solution comprising the drug danazol (0.5 g) and the solvent dichloromethane (4.5 g).
  • the particle mean diameter initially increased to 2.4 microns, and decreased within the next 20 hours to 0.35 microns after the drug solution was absorbed by the templating agent.
  • the organic solvent was stripped from the emulsion by evaporation and the continuous phase removed by freeze-drying, producing a white crystalline solid.
  • the white crystals were redispersed in water, initially giving particles with a mean diameter of 6.5 microns, which disintegrated within two hours to produce particles with a mean diameter of 0.3 microns.
  • the crystallinity of the danazol particles was verified by X-ray powder diffraction (FIG. 1).
  • the peak pattern of the danazol sample is essentially identical to the peak pattern of an untreated danazol control.
  • the improved bioavailability of the danazol particles was verified in an in-vivo study using rats who received 17.0 to 17.2 mg of danazol in a single oral gavage of capsules (FIGS. 3 A- 3 C).
  • the area under the curve (AUC) of the danazol template emulsion sample, shown in FIG. 3A, is clearly higher than the AUC's of the controls, i.e., danazol as received and physical mixtures of the drug danazol with the stabilizers Pluronic F-127 and polyvinylpyrrolidone 55 kD.
  • a template emulsion comprising triolein (7.5 g), polyvinylalcohol 9-10 kD (1.5 g), Span 80 (1.1 g), and water (7.5 g) was prepared with high shear mixing, giving template emulsion droplets with a mean diameter of 0.14 microns as measured by light scattering.
  • the template emulsion was mixed at ambient temperature with a solution comprising the drug danazol (0.5 g) and the solvent dichloromethane (4.5 g).
  • the particle mean diameter initially increased to 3.9 microns, and decreased within the next 20 hours to 0.4 microns after the drug solution was absorbed by the templating agent.
  • the organic solvent was stripped from the emulsion by evaporation and the continuous phase removed by freeze-drying, producing a white crystalline solid.
  • the white crystals were redispersed in water, initially giving particles with a mean diameter of 13.4 microns, which disintegrated within twelve hours to produce particles with a mean diameter of 0.8 microns.
  • a template emulsion comprising cottonseed oil (7.5 g), polyvinylalcohol 9-10 kD (7.5 g), and water (7.5 g) comprising 10 percent by weight Pluronic F-68 was prepared with high shear mixing, giving template emulsion droplets with a mean diameter of 0.3 microns as measured by light scattering.
  • the template emulsion was mixed at ambient temperature with a solution comprising the drug cyclosporin A (0.5 g) and the solvent toluene (2.2 g).
  • the particle mean diameter increased to 0.4 microns after the drug solution was absorbed by the templating agent and remained stable over at least 24 hours.
  • the organic solvent was stripped from the emulsion by evaporation and the continuous phase removed by freeze-drying, producing a white powder sample.
  • the white powder was redispersed in water, initially giving particles with a mean diameter of 14.5 microns, which disintegrated within five hours to produce particles with a mean diameter of 0.8 microns.
  • An aqueous template emulsion (5% in water) comprising stabilizer Atlox 4991 and methyloleate (12.5%) was prepared with high shear mixing.
  • the template emulsion was mixed at ambient temperature with a coarse drug emulsion comprising the drug cyclosporin A (10%), the solvent toluene (40%), the stabilizer Tween 40 (5%), and water (45%).
  • the initial particle mean diameter was 12.7 microns as measured by light scattering, but decreased to 3.6 microns after 15 minutes, 1.2 microns after 25 minutes, and 0.64 microns after 20 hours, while the drug emulsion was absorbed by the templating agent.
  • a template emulsion (35 g) comprising cottonseed oil (0.89%), polyvinylpyrrolidone 55 kD (2.68%), methyloleate (0.39%), and water (96.04%) was prepared with high shear mixing (10 minutes at 20,000 rpm) at ambient temperature, giving template emulsion droplets with a volume mean diameter of 0.28 microns as measured by light scattering.
  • the template emulsion was mixed at ambient temperature with a solution comprising the drug nifedipine (1 g) and the solvent toluene/isobutylacetate in a 60:40 mixing ratio (30 g), and the drug ketoconazole (1 g) and the solvent dichloromethane (9 g), respectively, as indicated in Table A.
  • the organic solvent was stripped from the emulsion by evaporation and the continuous phase removed by freeze-drying, producing a dry powder sample.
  • the powder sample was redispersed in deionized water.
  • the volume mean diameter of the oil droplets measured after addition of the drug solution, and the volume mean diameter of the drug particles after drying and redispersion in water are listed in Table A.
  • a template emulsion (13 g) comprising toluene (5%), polyvinylalcohol 9-10 kD (5%), Span 60 (0.37%), and water (89.6%) was prepared with high shear mixing (3 minutes at 20,000 rpm) at ambient temperature, giving template emulsion droplets with a volume mean diameter of 0.40 microns as measured by light scattering.
  • the template emulsion was mixed at ambient temperature with a solution comprising the drug naproxen, cyclosporin A, nifedipine, or ketoconazole (0.5 g), respectively, and the solvents dichloromethane (4.5 g) or toluene/isobutylacetate 60:40, as indicated in Table B.
  • the organic solvent was stripped from the emulsion by evaporation and the continuous phase removed by freeze-drying, producing a dry powder sample.
  • the powder sample was redispersed in deionized water.
  • the volume mean diameter of the oil droplets measured after addition of the drug solution, and the volume mean diameter of the drug particles after redispersion in water are listed in Table B.

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  • Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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EP (1) EP1467709A1 (de)
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AU (1) AU2003235686A1 (de)
CA (1) CA2470533A1 (de)
WO (1) WO2003059319A1 (de)

Cited By (3)

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US20080050450A1 (en) * 2006-06-26 2008-02-28 Mutual Pharmaceutical Company, Inc. Active Agent Formulations, Methods of Making, and Methods of Use
US20080102131A1 (en) * 2006-10-31 2008-05-01 Kaneka Corporation Particulate composition comprising bioactive substance and method of producing the same
US20100159010A1 (en) * 2008-12-24 2010-06-24 Mutual Pharmaceutical Company, Inc. Active Agent Formulations, Methods of Making, and Methods of Use

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AU2004229440B2 (en) 2003-04-10 2010-08-12 President And Fellows Of Harvard College Formation and control of fluidic species
CA2526454C (en) 2003-05-22 2013-08-13 Applied Nanosystems B.V. Gel-assisted production of small particles
WO2005021151A1 (en) 2003-08-27 2005-03-10 President And Fellows Of Harvard College Electronic control of fluidic species
AU2006280511A1 (en) * 2005-08-12 2007-02-22 Astrazeneca Ab Process
EP1962862B1 (de) * 2005-12-19 2013-09-04 Æterna Zentaris GmbH Alkylphospholipidderivate und deren verwendung
US20100068287A1 (en) * 2007-02-09 2010-03-18 Astrazeneca Ab Process for Preparation of a Stable Dispersion of Solid Amorphous Submicron Particles in an Aqueous Medium
WO2011049629A2 (en) 2009-10-22 2011-04-28 Api Genesis, Llc Methods of making and using compositions comprising flavonoids

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US5354556A (en) * 1984-10-30 1994-10-11 Elan Corporation, Plc Controlled release powder and process for its preparation
US6017559A (en) * 1994-07-15 2000-01-25 Dow Agrosciences Llc Preparation of aqueous emulsions
US6074986A (en) * 1993-09-15 2000-06-13 Mulqueen; Patrick Joseph Storage and dilution of stable aqueous dispersions

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US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US6074986A (en) * 1993-09-15 2000-06-13 Mulqueen; Patrick Joseph Storage and dilution of stable aqueous dispersions
US6017559A (en) * 1994-07-15 2000-01-25 Dow Agrosciences Llc Preparation of aqueous emulsions

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080050450A1 (en) * 2006-06-26 2008-02-28 Mutual Pharmaceutical Company, Inc. Active Agent Formulations, Methods of Making, and Methods of Use
US20080220076A1 (en) * 2006-06-26 2008-09-11 Mutual Pharmaceutical Company, Inc. Active Agent Formulations, Methods of Making, and Methods of Use
US20080102131A1 (en) * 2006-10-31 2008-05-01 Kaneka Corporation Particulate composition comprising bioactive substance and method of producing the same
US20100159010A1 (en) * 2008-12-24 2010-06-24 Mutual Pharmaceutical Company, Inc. Active Agent Formulations, Methods of Making, and Methods of Use

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EP1467709A1 (de) 2004-10-20
CA2470533A1 (en) 2003-07-24
JP2005515224A (ja) 2005-05-26
WO2003059319A1 (en) 2003-07-24

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